This invention relates to compounds which inhibit lipoxygenase enzymes. It also relates to methods of inhibiting lipoxygenase enzymes in human and animal hosts in need of such treatment.
The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of potent biological mediators, the leukotrienes (LTs). Similarly 12- and 15-lipoxygenase convert arachidonic acid to 12- and 15-HPETE respectively. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins. 12-HETE has been found in high levels in epidermal tissue of patients with psoriasis. Lipoxins have recently been shown to stimulate elastase and superoxide ion release from neutrophils.
A variety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they have been implicated as mediators in various disease states. For example, the LTs C.sub.4 and D.sub.4 are potent constrictors of human airways in vitro and aerosol administration of these substances to non-asthmatic volunteers induces bronchoconstriction. LTB4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of rheumatoid arthritic patients. Leukotrienes have been implicated as important mediators in asthma, allergic rhinitis, rheumatoid arthritis, psoriasis, adult respiratory distress syndrome, gout, inflammatory bowel disease, endotoxin shock, Crohn's disease, and ischemia induced myocardial injury. The biological activity of the LTs has been reviewed by Lewis and Austen, J. Clinical Invest. 73, 89, 1984 and by J. Sirois, Adv. Lipid Res., 21, 78, (1985).
Thus, lipoxygenase enzymes are believed to play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, and inflammation. Agents which block or modulate the activity of lipoxygenase enzymes will likely be useful in the treatment of diseases involving leukotriene pathogenesis. Some examples of 5-lipoxygenase inhibitors known to the art are: AA-861, disclosed in U.S. Pat. No. 4,393,075, issued Jul. 12, 1983, to Terro et al., pyrazolopyridines, disclosed in European Patent Application of Iriburn et al., Ser. No. 121,806, published Oct. 17, 1984; arachidonyl hydroxamic acid, disclosed in E. J. Corey et al., J. Am. Chem. Soc., 106, 1503 (1984) and European Patent Application of P. H. Nelson, Ser. No. 104, 468, published Apr. 4, 1984; BW-755C, disclosed in Radmark et al., FEBS Lett, 110, 213, (1980); nordihydroguaiaretic acid, disclosed in Marris et al, Prostaglandins, 19, 371 (1980); Rev-5901, disclosed in Coutts, Meeting Abstract 70, Prostaglandins and Leukotrienes '84; benzoxaprofen, disclosed in J. Walker, Pharm. Pharmacol., 31, 778 (1979), and hydroxamic acids, disclosed in U.S. Pat. Nos. 4,608,390 and 4,623,661, issued Aug. 16, and Nov. 18, 1986 respectively.